Transdermal drug delivery device using a polymer-filled microporous membrane to achieve delayed onset

ABSTRACT

A delayed onset transdermal drug delivery device exhibiting a delay period of at least six hours comprising a laminated composite of (12) a top backing layer; (13) a pressure rupturable layer underlying (12); (14) a reservoir of a solution of drug in a liquid vehicle between (12) and (13); (16) a wick layer underlying (13) for dispersing the drug once (13( is ruptured; (17) a polymer layer underlying (16) that is permeable to the drug; (18) a microporous membrane underlying (17) which is itself impermeable to the drug but whose pores are filled with a polymer that is immiscible in the adhesive and has a solubility parameter within two units of the solubility parameter of the vehicle; and (20) an adhesive layer underlying (18) that is permeable to the drug but is immiscible in the polymer filling the pores of (6).

TECHNICAL FIELD

This invention is in the general field of transdermal drug delivery andrelates specifically to devices from which drug is released in a delayedpattern from the time the device is placed on the skin. Devices thatrelease drug in such a pattern are commonly referred to as "delayedonset" devices.

BACKGROUND

Earnest efforts to develop transdermal drug delivery devices thatprovide drug to the patient in a controlled pattern began in the late1960s and early 1970s. The principal pattern of delivery that wasinvestigated was substantially constant rate delivery in which deliverybegan at or shortly after the device was applied to the skin, rose to adesired level, and stayed at that level for a sustained time period.These efforts resulted in numerous patents being issued for devices ofvarious structures that achieved or closely mimicked constant ratedelivery. See, for instance, U.S. Pat. Nos. 3,598,122; 3,598,123;3,797,494; and 4,286,592.

Nitroglycerin (NTG) is among the many drugs that has been administeredtransdermally. Among the U.S. patents describing transdermal NTGdelivery are U.S. Pat. Nos. 3,742,951; 4,533,540; 4,559,222; 4,618,699;4,681,584; 4,654,209; 4,655,766; 4,661,441; 4,751,087; 4,776,850;,4,778,678; 4,784,857; and 4,786,282. None of these patents concerndelayed onset nitroglycerin delivery. Further, the initial commercialtransdermal NTG devices (the Transderm-Nitro and Nitro-Dur devices) arecontinuous rather than delayed-onset delivery devices.

In the mid-1980s a number of clinical studies raised questions about theefficacy of NTG therapy provided by the then available commercialtransdermal devices that administered NTG in a continuous pattern.Specifically, continuous administration was tending to cause toleranceand hemodynamic attenuation. This led clinicians to conclude that theideal regimen for administering NTG would include an overnight "washoutperiod" during which no NTG was administered. Correlatively, it leddevelopers of transdermal devices to propose delayed onset devices foradministering NTG.

U.S. Pat. No. 4,956,181 describes a delayed onset device foradministering NTG. Its device consists of a backing layer, a rupturablepod sandwiched between the backing and a nonwoven fabric layer, abarrier membrane, an adhesive layer, and a release liner. The rupturablepod contains NTG and an activator liquid that is capable of plasticizingthe barrier membrane and increasing its permeability to NTG. Once thepod is ruptured, drug and activator migrate down through the barriermembrane, with the activator causing the membrane to become increasinglypermeable to the drug. While this patent indicates that an effectivedelay of up to 12 hr may be achieved, the examples of the patentdescribe devices that achieve only a 4-6 hr delay.

An object of the present invention is to provide a delayed onset devicefor administering NTG that provides at least a six and preferably aneight hour delay in administration. The device of the invention does notuse plasticization of a barrier membrane as a delay mechanism.

DISCLOSURE OF THE INVENTION

This invention is a device for administering a drug transdermallyfollowing application of the device to a subject's skin wherein thedelivery of drug is delayed at least about six hours after saidapplication comprising in combination: (a) a nonrupturable backing layerforming the top surface of the device; (b) a pressure rupturablereservoir underlying (a) and containing the drug dissolved in a liquidvehicle; (c) a wick layer underlying (b) for dispersing the drug oncethe reservoir is ruptured; (d) a layer of a drug permeable polymerunderlying (c); (e) a microporous membrane underlying (d); (f) a layerof a drug permeable adhesive polymer underlying (e) and forming thebasal layer of the device wherein the pores of the membrane are filledwith a polymer that is immiscible in the polymer of (d) and (f) and hasa solubility parameter that is within two units of the solubilityparameter of the vehicle; and wherein it initially takes at least aboutsix hours for the drug to diffuse to the skin from the reservoir oncethe reservoir is ruptured and the device is applied to the skin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a sectional view of an embodiment of the invention foradministering NTG. The drawing is not to scale. The thicknesses of thelayers of the embodiment are exaggerated for the purposes ofillustration.

FIG. 2 is a graph of the results of the tests described in Example 1.

MODES FOR CARRYING OUT THE INVENTION

The drawing shows a preferred embodiment, generally designated 11, ofthe delayed onset device of the invention. The top surface of the deviceis defined by backing layer 12. It is made of a material or combinationof materials that is substantially impermeable to the solution of NTG inthe liquid vehicle, does not absorb significant amounts of the NTGsolution, and is capable of being sealingly bonded (e.g., by heatsealing or crimping) at its periphery to the underlying microporousmembrane layer 18 (described below). In addition, the mechanicalproperties of the backing should be such that it does not rupturecoincident with the rupture of the underlying rupturable layer 13. It isalso preferably flexible and/or elastomeric. Examples of materials fromwhich the backing layer may be formed are elastomeric polymers such aspolyether block amide copolymers (e.g., PEBAX copolymers), polyethylenemethyl methacrylate block copolymers, (e.g., NUKRELL polymers),polyurethanes (e.g., PELLATHANE polymers), silicone elastomers,polyester block copolymers such as HYTREL, rubber-based polyisobutylene,styrene, and styrene-butadiene and styrene-isoprene copolymers. Flexiblepolymers include polyethylene, polypropylene, and polyesters such aspolyester terephthalate (PET), which may be provided as films orlaminates. The thickness of the backing layer will normally be in therange of 0.01 to 0.15 mm, more normally 0.02 to 0.1 mm. The backing mayoptionally be pigmented (e.g., to resemble skin color).

Backing layer 12 has a cavity that serves as a reservoir or containerfor a liquid formulation of NTG, generally designated 14. Formulation 14comprises NTG in a liquid vehicle. Examples of suitable liquid carriersare lower alkanols such as methanol, ethanol, isopropanol, glycols suchas propylene glycol, and the like. Propylene glycol is preferred. Thesolubility parameter of propylene glycol is 12.6 (cal/cm³)^(1/2). Theformulation may also contain additional ingredients such as a dye whichmay serve as an indicator of rupture of the reservoir. The NTG willnormally comprise 2 to 20% by weight of the formulation, more normally 5to 10% by weight. The total amount of NTG in the reservoir will normallybe 50 to 300 mg, more normally 100 to 150 mg.

Directly underlying the cavity and backing layer is apressure-rupturable layer 13. Layer 13 is sealed to the overlyingbacking layer 12 (and underlying layers to the microporous membranelayer 18) about the periphery of the cavity containing the NTGformulation 14. Layer 13 is also impermeable to the NTG formulation andserves as the basal wall of the reservoir. It is made of a material thatmay be ruptured with normal finger pressure such as aluminum foil coatedwith a heat sealable layer of ethylene vinyl acetate copolymer,polypropylene or polyethylene. Underlying layer 13 in registry with thereservoir is a hard, solid (incompressible) body 15 to which fingerpressure may be applied to facilitate the rupture or tearing of layer 13below the reservoir to release the liquid formulation of NTG from thereservoir. The body is smaller in dimension than the cavity containingthe NTG solution. It will typically be made from hard materials such aspolycarbonate, polypropylene, or high density polyethylene.

Immediately below the rupturable layer 13 is a wick layer 16 that iscapable of dispersing or spreading the liquid formulation of NTGtransversely (parallel) to the basal surface of the device. The wicklayer does not absorb or retain any substantial amount of the NTGformulation and functions merely to spread the formulation across thedevice. It is not a barrier to diffusion of the NTG from the reservoirto the skin surface. The wick layer is preferably made from a nonwovenpolymeric fabric such as spun-bonded polyester. It will normally have abasis weight of 0.2 to 1 oz./yard², preferably 0.4 to 0.6 oz./yard². Thewick layer must be capable of adhering to the adjoining layers of thedevice under conditions of use (i.e., in the presence of adsorbed NTGformulation) and be sealable (e.g., by heat) to the overlying layers andto the underlying microporous membrane.

Underlying the wick layer 16 is a first layer of a polymer adhesivelayer 17 that is permeable to the NTG formulation. The diffusioncoefficient of NTG in this layer will normally be 1×10⁻⁷ to 1×10⁻⁸cm/sec. Its thickness will normally be 0.02 to 0.3 mm, more usually 0.02to 0.15 mm.

The next layer is a microporous membrane layer 18. The material fromwhich the membrane itself is made is substantially impermeable to theNTG formulation and to the adhesive of layers 17 and underlying adhesivelayer 20. Examples of microporous materials are microporouspolypropylene (CELGARD, Hoechst-Celanese), microporous polyethylene(COTRAN, 3M), and microporous polytetrafluoroethylene (TEFLON, Gortex).The membrane will typically have a pore volume in the range of 10% to60%. The pores are filled with a polymer 19 that is substantiallyimmiscible with the adhesive of layers 17 and 20 and has a solubilityparameter within about two units (units expressed in (cal/cm³)^(1/2)).The immiscibility of the polymer with the adhesive deters the adhesivefrom migrating into the pores during storage. The similarity of thesolubility parameter of the polymer to the vehicle permits the NTGformulation to permeate through the polymer. An example of a polymerthat may be used to fill the membrane pores is polyethylene oxide (m.w.100,000 to 600,000). The thickness of the microporous membrane layerwill normally be 0.001 to 0.1 mm.

As indicated, a second adhesive layer 20 underlies the microporousmembrane. The second adhesive layer may have the same or differentcomposition as the first layer. The thickness of the second adhesivelayer will normally be 0.02 to 0.3 mm, more usually 0.02 to 0.15 mm.Examples of adhesives from which the adhesive layers 17 and 20 may bemade are polysiloxanes, polyacrylates, polyurethanes, and ethylene-vinylacetate copolymers.

A standard release liner layer 22 underlies the second adhesive layer.

The delayed onset devices of the present invention are designed to beworn for a one-day period and then replaced. In the case of NTG, thedevices will normally be placed on the skin shortly before theindividual goes to sleep at night. Thus, the period during which thewearer receives insignificant NTG will coincide roughly with thewearer's sleeping hours; whereas the period during which delivery iseffected will coincide roughly with the wearer's waking hours. Thispattern of delivery provides NTG when most needed--upon awakening andthrough the day--and allows the level of NTG in the wearer's circulationto wash out or decline during sleep so that tolerance to NTG islessened.

In use, the device is removed from its packaging and gripped such that aforce may be applied from the basal surface against the solid body 15 tocause the solid body to penetrate and rupture layer 13. The releaseliner layer is then removed and the device is placed on the skin withthe basal layer of the second adhesive layer 20 in drug-delivery contactwith the skin surface. The rupturing of layer 13 permits the liquid NTGformulation 14 to be released onto the wick layer 16. The adsorbentproperties of the wick layer cause the liquid to be dispersed across(parallel to the basal surface) the device. The liquid then diffusesthrough the first adhesive layer, the polymer-filled pores of themicroporous membrane layer, and the second adhesive layer. The NTG isreleased from the basal surface of the second adhesive layer into theskin. The extent of the delayed onset will depend upon the diffusioncoefficients of the polymers forming the first and second adhesivelayers, the thicknesses of those two layers, the porositycharacteristics of the microporous membrane, the thickness of themicroporous membrane, and the solubility parameter of the polymerfilling the membrane pores. With the ranges of these parameters givenabove a delay of at least eight hours is achieved before skin flux ofNTG reaches about 2 μg/cm² /hr. During the delay period the NTG skinflux ranges between 0 and about 2 μg/cm² /hr. After the delay period theskin flux rises steadily over the remainder of the 24-hour wearingperiod to a skin flux level of about 5 to 20 μg/cm.sup. 2 /hr. Theselevels of skin flux are as measured by the in vitro diffusion; allstudies described in the Examples, infra. The drug delivery area of thedevice (i.e., the basal surface) is normally in the range of 10-50 cm²,preferably 15-25 cm².

The devices of the invention may be made by conventional laminationtechniques. By way of example, a cavity of desired size is formed in abacking layer. The cavity is filled with a 10% solution of NTG inpropylene glycol. The rupturable foil layer is then placed over thecavity. Two sheets of release liner are then coated on one side withadhesive to the desired thickness. One of these sheets is laminated tothe wick layer and the release liner is removed. A polymer-filledmicroporous membrane is then laminated to the exposed side of theadhesive layer and the other adhesive-release liner subassembly islaminated to the other side of the polymer-filled microporous membrane.The pores of the membrane may be filled with the polymer either bycoating the polymer from solution onto the membrane surface and heatingthe coated membrane, dipping the membrane into molten polymer, orplacing films of the polymer on both sides of the membrane andhot-rolling the subassembly. Finally the backing-NTG reservoir,rupturable layer subassembly is laminated to the wick layer onto which a1 cm diameter, 2 mm thick disc of polycarbonate has been placed and theassembly is heat-sealed about the periphery of the cavity, therebyheat-sealing the backing through to the microporous membrane layers.

The following examples further describe the invention. These examplesare not intended to limit the invention in any manner.

EXAMPLE 1

Water-based acrylic adhesive (Flexcryl 1625, 69% solids) was coated ontoa 0.003" thick siliconized polyester release liner film at a thicknessof 0.005". The adhesive coating was cured at 70° C. for 30 min in orderto remove water; cured thickness was 0.002" (5 mg/cm²). Two such filmswere prepared.

About 2 g of a polyethylene oxide (PEO) powder (POLYOX WSRN-10 fromUnion Carbide Corp.) was dispersed into about 31 g of water withconstant stirring over a period of 10 min. About 1% by weight of anonionic surfactant (Triton X-100) was then added. The resulting mixturewas coated onto a microporous membrane (CELGARD 2400 fromHoechst-Celanese) at 0.015". The coated membrane was exposed to 67° C.for 60 hr, in which time the CELGARD turned transparent.

One of the two adhesive coated release liner films was laminated to apolyester nonwoven (Reemay 2250). The release liner was removed and thefilled CELGARD was laminated to this exposed surface such that thecoated side faced the nonwoven. The other side was laminated to thesecond adhesive film. A disc of this multilaminate was die-cut andlaminated to the stratum corneum side of a disc of human cadaverepidermis, using the second adhesive.

A disc of the skin/multilaminate composite was mounted on a glassdiffusion cell (effective flux area 0.71 cm²) with the skin side facingthe receptor compartment. The donor was 37 μl of a 10% nitroglycerinsolution in propylene glycol (SDM 27 from ICI Americas). This solutionwas placed in the donor compartment directly in contact with thenonwoven. The donor compartment was then occluded, and the cellmaintained at 32° C. Samples of the receiving solution were takenperiodically and analyzed by HPLC to determine the amount ofnitroglycerin permeated in unit time. The experiment was repeatedexactly, substituting Nitro-Dur, a commercially available transdermaldevice, for the multilaminate layer and nitroglycerin vehicle.

As shown in FIG. 2, Nitro-Dur reached substantial flux in 2-4 hr afteradministration, whereas the composite of the invention delayed fullonset to 8 hr after administration.

EXAMPLE 2

Films of polyethylene oxide (PEO) were prepared by pouring a uniformlayer of the powder onto the release side of a 0.003" thick siliconizedpolyester film. A second siliconized polyester film is then placedrelease side down on top of the PEO powder. This was pressed on a Carverpress for 4 minutes at 100° C. and 24,000 psi between two stainlesssteel plates. Two PEO films of approximately 3 mils were prepared. Themicroporous membrane (CELGARD 2400 from Hoechst-Celanese) was sandwichedbetween these two PEO films and pressed on the Carver press for 4minutes at 100° C. and 20,000 psi. This creates the pore-filledmicroporous membrane. An excess of PEO is used resulting in a layer ofPEO on either side of the microporous membrane. Water-based acrylicadhesive (Flexcryl 1625, 69% solids) was coated onto a 0.003" thicksiliconized polyester film at a thickness of 0.005". The adhesivecoating was cured at 70° C. for 30 minutes in order to remove all of thewater; cured thickness was 0.002" (5 mg/cm²). Two adhesive films wereprepared. The pore-filled microporous membrane is laminated to the oneadhesive layer. The second adhesive film was laminated to the polyesternonwoven (Reemay 2250). The siliconized release liner is removed and theadhesive with the nonwoven is then laminated to the exposed microporousmembrane surface. A disc of this multilaminate was die-cut and tested inskin flux studies as in Example 4, including comparison testing withNitro-Dur.

The results were substantially the same as those for Example 1.

While the invention has been exemplified in terms of an embodiment foradministering NTG, it may also be used to administer other drugs in adelayed onset regimen. Drugs which may be advantageously administered insuch a regimen include other vasodilators, analgesics, contraceptives,appetite suppressants, growth factors, and the like. Other modificationsof the above-described modes for carrying out the invention that areobvious to those of skill in the fields of transdermal drug deliverydevice design, materials science, polymer chemistry and related fieldsare intended to be within the scope of the following claims.

We claim:
 1. A device for administering a drug transdermally followingapplication of the device to a subject's skin wherein the delivery ofdrug is delayed at least about six hours after said applicationcomprising in combination:(a) a nonrupturable backing layer forming thetop surface of the device: (b) a pressure rupturable reservoirunderlying (a) and containing the drug dissolved in a liquid vehicle;(c) an adsorbent wick layer underlying (b) for dispensing the drug oncethe reservoir is ruptured; (d) a layer of a drug permeable polymeradhesive underlying (c); (e) a microporous polymer membrane underlying(d), the polymer of which is impermeable to the solution of drug in theliquid vehicle; (f) a layer of a drug permeable adhesive polymerunderlying (e) and forming the basal layer of the device wherein thepores of the membrane are filled with a polymer that is substantiallyimmiscible in the polymers of (d) and (f), and has a solubilityparameter that is within two units of the solubility parameter of thevehicle, wherein it initially takes at least about six hours for thedrug to diffuse to the skin from the reservoir once the reservoir isruptured and the device is applied to the skin.
 2. The device of claim 1wherein the reservoir is defined by a cavity formed between the backinglayer and a pressure rupturable layer overlying the wick layer.
 3. Thedevice of claim 2 including means for transmitting manually appliedpressure to the pressure rupturable layer.
 4. The device of claim 3wherein the means is an incompressible body underlying the pressurerupturable layer.
 5. The device of claim 4 wherein the pressurerupturable layer is a metal foil layer.
 6. A delayed onset device foradministering nitroglycerin transdermally to a subject's skin comprisingin combination:(a) a nonrupturable backing layer forming the top surfaceof the device; (b) a pressure rupturable reservoir underlying (a) andcontaining a solution of nitroglycerin in propylene glycol; (c) anadsorbent wick layer underlying (b) for dispersing the nitroglycerinonce the reservoir is ruptured; (d) a first layer of a nitroglycerinpermeable polymer adhesive underling (c); (e) a microporous polymermembrane underling (d) the polymer of which is impermeable to thesolution of nitroglycerin; (f) a second layer of nitroglycerin permeableadhesive polymer underlying (e) and forming the basal surface of thedevice, wherein the pores of the membrane are filled with a polymer thatis substantially immiscible in the adhesive polymers of (d) and (f) andhas a solubility parameter within two units of the solubility parameterof propylene glycol and it initially takes at least about eight hoursfor the nitroglycerin to diffuse to the skin from the reservoir once thereservoir is ruptured and the device is applied to the skin.
 7. Thedevice of claim 6 wherein the polymer filling the pores of the membraneis high molecular weight polyethylene oxide.
 8. The device of claim 7wherein the diffusion coefficient of nitroglycerin in the adhesivepolymers of (d) and (f) are 1×10⁻⁷ cm/sec to 1×10⁻⁸ cm/sec.
 9. Thedevice of claim 8 wherein the adhesive polymer is an acrylic polymer.10. The device of claim 6 wherein the skin flux during said at leastabout six hours is less than 2 μg/cm² /hr and thereafter rises to about5 to 20 μg/cm² /hr.
 11. The device of claim 6 wherein the reservoir isdefined by a cavity formed between the backing layer and a pressurerupturable layer overlying the wick layer.
 12. The device of claim 11including means for transmitting manually applied pressure to thepressure rupturable layer.
 13. The device of claim 12 wherein the meansis an incompressible body underlying the pressure rupturable layer. 14.The device of claim 9 wherein the skin flux during said at least aboutsix hours is less than 2 μg/cm² /hr and thereafter rises to about 5 to20 μg/cm² /hr.
 15. The device of claim 1 wherein the drug is avasodilator, analgesic, contraceptive, appetite depressant, or growthfactor; the pressure rupturable reservoir is comprised of a metal foilcoated with a layer of a heat-sealable polymer; the wick layer isnonwoven; and the material forming the microporous membrane ispolypropylene, polyethylene, or polytetrafluoroethylene.
 16. The deviceof claim 15 wherein the metal foil is aluminum foil and theheat-sealable polymer is ethylene vinylacetate copolymer, polyethylene,or polypropylene.
 17. The device of claim 6 wherein the pressurerupturable reservoir is comprised of a metal foil coated with a layer ofa heat-sealable polymer; the wick layer is nonwoven; the polymer fillingthe pores of the microporous membrane is polyethylene oxide; and thematerial forming the microporous membrane is polypropylene,polyethylene, or polytetrafluoroethylene.
 18. The device of claim 17wherein the metal foil is aluminum foil and the heat-sealable polymer isethylene vinylacetate copolymer, polyethylene, or polypropylene.